Elevated levels of blood cholesterol and blood lipids are conditions which are believed related to the onset of arteriosclerosis. Thus, compounds capable of reducing the levels of these blood constituents are recognized as potentially useful anti-arteriosclerotic agents.
The compounds of the present invention are useful as anti-arteriosclerotic agents and are capable of elevating the high density lipoprotein fraction of cholesterol (HDL-C), and this effect is known to lower the risk factor of coronary heart disease (Gordon, T. et al., High Density Liproprotein as a Protective Factor Against Coronary Heart Disease, May 1977, The American Journal of Medicine, Vol. 62, pp. 707-714). There is strong support for the concept that induced lowering of the low density lipoprotein fraction of cholesterol (LDL-C) will reduce the risk for coronary heart disease in hypocholesteremic patients (JAMA 251:361 and 365, 1984). Certain compounds of the invention also are able to reduce the LDL-C, thus further reducing the risk factor of coronary heart disease.
British Pat. No. 2,053,215 covers certain benzimidazole derivatives of the structural formula ##STR1## used as hypolipidemics.
One aspect of the present invention is a compound of the formula ##STR2## wherein X is CH or N; R.sub.1 and R.sub.2 are the same or different and are hydrogen, halogen, straight or branched alkyl or alkoxy of from one to six carbon atoms, or CF.sub.3 ; n is an integer of from three to six; R.sub.4 and R.sub.5 are the same or different and are a straight or branched alkyl of from one to six carbon atoms or when R.sub.4 and R.sub.5 are taken together are --(CH.sub.2).sub.p wherein p is an integer of from two to five; R.sub.6 is hydrogen, a straight or branched alkyl of from one to six carbon atoms, an alkali or alkaline earth metal cation, an organic amino cation, or ammonium; R.sub.3 is hydrogen, an alkyl of from one to six carbon atoms which may be substituted by hydroxy, aryl, CO.sub.2 R.sub.6 or the group ##STR3## wherein R.sub.4, R.sub.5, and R.sub.6 are as defined above; or a pharmaceutically acceptable acid addition salt thereof.
Another aspect of the present invention is a method of preparing a compound of formula I above which comprises reacting an optionally substituted benzimidazole phenol with a halogenated, alkyl-substituted carboxylic acid ester to produce the desired product and converting, if desired, to the pharmaceutically acceptable acid addition or base salts thereof.
Yet another aspect of the present invention is another method of preparing a compound of formula I above which comprises reacting a formylphenoxy substituted carboxylic acid ester with a substituted phenylene diamine to form the desired product and converting, if desired, to the pharmaceutically acceptable acid addition or base salts thereof.
A fourth aspect of the present invention is a pharmaceutical composition useful for treating arteriosclerosis in a mammal which comprises an effective amount of a compound of formula I above in combination with a pharmaceutically acceptable carrier in unit dosage form.
A fifth aspect of the present invention is a method of treating arteriosclerosis in mammals in need of such treatment which comprises administering an effective amount of the above defined pharmaceutical composition to said mammal.